Compounds (A) to (AL) listed below, their preparation as well as the pharmacological activity of these compounds based on inhibition of kinases, e.g., VEGFR-2, suitable for therapy in oncology, are disclosed in WO 02/36564, WO 99/52869, WO 00/18734, WO 00/73297, WO 01/27080, WO 01/27081 and WO 01/32651. The cited documents are herewith incorporated by reference.
Lck, a further tyrosine kinase belonging to the src family of tyrosine kinases not mentioned in the references cited above, is functionally required for T-cell activation through the T-cell antigen receptor (TCR) (see A. E. Nel: T-cell activation through antigen receptor. Part 1: Signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse. J. Allergy Clin Immunol, 109, 5, 758-770, 2002) and possibly T-cell survival (Seddon, B.; Legname, G.; Tomlinson, P.; Zamoyska, R.: Long-term survival but impaired homeostatic proliferation of naive T cells in the absence of p56(lck). Science 290: 127-131, 2000). Therefore, any Lck inhibitor has a high possible therapeutic potential in the treatment of T-cell mediated diseases, e.g., in the treatment of immunologic diseases. Certain autoimmune diseases such as inflammatory diseases (for example, inflammatory bowel disease, rheumatoid arthritis, glomerulonephritis and lung fibrosis, psoriasis, hypersensitivity reactions of the skin, atherosclerosis, restenosis, allergic asthma, multiple sclerosis and type 1 diabetes) are believed to be associated with inappropriate T cell activation (J. H. Hanke et al., Inflamm. Res., 1995, 357). In addition, the acute rejection of transplanted organs as well as Graft versus Host Disease (GvHD) after allogeneic bone marrow and stem cell transplantation can also be interpreted as a consequence of inappropriate T cell activation. Lck inhibitors offer an approach for treatment of the indications mentioned hereinbefore. Agents of this kind would offer therapy for transplant rejection and autoimmune diseases whilst avoiding toxicities associated with the commonly used, less selective immunosuppressants. The leading agent for prevention or treatment of transplant rejection is cyclosporin A which, although effective, is often associated with side-effects such as renal damage and hypertension, which results in kidney failure in a substantial number of patients. It is contemporary practice to treat rheumatoid arthritis initially with symptom relief agents such as NSAIDs, which have no effect on disease progression and are often associated with unwanted side-effects. A rationally based, disease modifying agent, without such deleterious side-effects, would therefore offer significant benefits in the prevention or treatment of transplant rejection or autoimmune conditions such as rheumatoid arthritis.
There is considerable evidence that VEGF plays a key role in the pathogegenesis in rheumatoid arthritis, especially in the formation of the pannus (Paleolog E M, Arthritis Res 2002; 4 Suppl 3:S81-90, Pavonen et al, J Rheumatol 2002 January; 29(1):39-45, Afuwape A O et al, Histol Histopathol 2002; 17(3):961-72). Thus, combined inhibition of VEGFR-tyrosine kinases and Lck is considered of potentially high benefit for patients with this disease. The same considerations can be applied to psoriasis and inflammatory bowel disease (Folkman J, Nat. Med. 1995 January; 1(1):27-31. Review; Griga T et al, Hepatogastroenterology 2002 January-February; 49(43): 116-23, Creamer D et al, Arch Dermatol 2002 June; 138(6):791-6).